Chronic lung diseases share the common feature of epithelial repair defects and fibroproliferation that contribute to loss of tissue homeostasis and further deterioration of lung function. There is growing support for the notion that signaling changes between epithelial cells and fibroblasts are key factors that drive defective epithelial maintenance/repair and tissue remodeling. Goals of this proposal are to improve our ability regulate epithelial progenitor cells in health and disease, and to develop strategies to enhance epithelial regeneration. We have developed mouse lines and cell fractionation strategies that when coupled with a novel in vitro culture model allow us to quantify growth and differentiation of airway progenitor cells in small molecule screening assays. Expansion of epithelial progenitor cells is dependent upon stromal cell interactions that recapitulate cell-cell interactions in the intact lung that mediate normal tissue maintenance or remodeling. Goals of this application are to exploit this assay to screen a library of pharmacologically active small molecules to identify potentially novel therapeutics that can modulate epithelial progenitor cell growth and differentiation in vitro (Aim 1). Aim 2 will perform secondary assays to optimize lead compounds defined in Aim 1 and determine their ability to enhance epithelial growth in an in vitro model of idiopathic pulmonary fibrosis. Results from this application will identify chemical tools for manipulation of signaling pathways that regulate epithelial growth and differentiation. These studies will provide new information for the development of drugs capable of enhancing epithelial repair and restoration of lung function to patients with chronic lung disease.